Chronic lymphocytic leukemia is the most common adult leukemia in Western countries, with an estimated incidence of 3.9 per 100,000 people in the US and a median age of 72 years at time of diagnosis. A characteristic feature of this disease is its strikingly complex genomic profiles, highlighted by chromosome structural aberrations involving loss of chromosomes 11q, 13q, 17p and trisomy 13 [4,5]. These complex genetic alterations are thought to arise due to the stepwise accumulation of mutational changes in favor of tumor progression, initially in a genetically heterogeneous cell population, then by selection of more aggressive traits, such as the ability to metastasize into surrounding tissues. One important mechanism that protects against the acquisition of an unstable genome is proper function of telomeres, protein-DNA complexes that cap the ends of chromosomes. Dysfunctional telomeres undergo end-to-end chromosome fusions, resulting in an unstable genome observed in many diverse human cancers, including CLL. We hypothesize that telomere dysfunction in hematopoietic stem cells (HSCs) results in telomere dysfunction, driving genomic instability that results in the stepwise accumulation of mutational changes in favor of cancer progression, including the selection of p53 mutations during clonal evolution and progression to CLL. To test this hypothesis, we have generated a novel conditional knockout mouse model to delete mPOT1a/b in hematopoietic stem cells. As pioneers in the study of the role of POT1 in telomere end protection, we will utilize this highly innovative genetic tool, as wel as human CLL samples, to investigate the role of hPOT1 in CLL pathogenesis.